1. Field of the Invention
It has become increasingly clear in recent years that cell death is as important to the health of a multicellular organism as cell division: where proliferation exists, so must a means of regulating its cellular progeny. By repeated cell division and differentiation throughout development or tissue repair, surplus or even harmful cells are generated, and they must be removed or killed. In adults, senescent cells are removed and replaced by newly generated cells to maintain homeostasis.
The delicate interplay between growth and cell death in an organism is mirrored in the complex molecular balance that determines whether an individual cell undergoes division; arrests in the cell cycle; or commits to programmed cell death. Signal transduction is the term describing the process of conversion of extracellular signals, such as hormones, growth factors, neurotransmitters, cytokines, and others, to a specific intracellular response such as gene expression, cell division, or apoptosis. This process begins at the cell membrane where an external stimulus initiates a cascade of enzymatic reactions inside the cell that typically include phosphorylation of proteins as mediators of downstream processes which most often end in an event in the cell nucleus. The checks and balances of these signal transduction pathways can be thought of as overlapping networks of interacting molecules that control “go-no go” control points. Since almost all known diseases exhibit dysfunctional aspects in these networks, there has been a great deal of enthusiasm for research that provides targets and therapeutic agents based on signal transduction components linked to disease.
Dysregulation of cell proliferation, or a lack of appropriate cell death, has wide ranging clinical implications. A number of diseases associated with such dysregulation involve hyperproliferation, inflammation, tissue remodelling and repair. Familiar indications in this category include cancers, restenosis, neointimal hyperplasia, angiogenesis, endometriosis, lymphoproliferative disorders, graft-rejection, polyposis, loss of neural function in the case of tissue remodelling, and the like. Such cells may lose the normal regulatory control of cell division, and may also fail to undergo appropriate cell death.
In one example, epithelial cells, endothelial cells, muscle cells, and others undergo apoptosis when they lose contact with extracellular matrix, or bind through an inappropriate integrin. This phenomenon, which has been termed “anoikis” (the Greek word for “homelessness”), prevents shed epithelial cells from colonizing elsewhere, thus protecting against neoplasia, endometriosis, and the like. It is also an important mechanism in the initial cavitation step of embryonic development, in mammary gland involution, and has been exploited to prevent tumor angiogenesis. Epithelial cells may become resistant to anoikis through overactivation of integrin signaling. Anoikis resistance can also arise from the loss of apoptotic signaling, for example, by overexpression of Bcl-2 or inhibition of caspase activity.
An aspect of hyperproliferation that is often linked to tumor growth is angiogenesis. The growth of new blood vessels is essential for the later stages of solid tumor growth. Angiogenesis is caused by the migration and proliferation of the endothelial cells that form blood vessels.
In another example, a major group of systemic autoimmune diseases is associated with abnormal lymphoproliferation, as a result of defects in the termination of lymphocyte activation and growth. Often such diseases are associated with inflammation, for example with rheumatoid arthritis, insulin dependent diabetes mellitus, multiple sclerosis, systemic lupus erythematosus, and the like. Recent progress has been made in understanding the causes and consequences of these abnormalities. At the molecular level, multiple defects may occur, which result in a failure to set up a functional apoptotic machinery.
The development of compounds that inhibit hyperproliferative diseases, particularly where undesirable cells are selectively targeted, is of great medical and commercial interest.
2. Description of the Related Art
Triazolylated tertiary amine compounds are provided in U.S. Pat. No. 5,674,886. U.S. Pat. Nos. 4,101,548 and 4,171,363 disclose quinazoline compounds, and in particular 2-piperazinyl-6,7-dimethoxyquinazolines compounds that include a 1,2,3-thiadiazole terminal group. U.S. Pat. Nos. 3,787,434 and 3,874,873 disclose herbicidal compounds and compositions that include 1,2,3-thiadiazole-5-yl ureas.
Chemical compounds are disclosed in Tarasov et al., Khim. Geterotsikl. Soedin. 8:1124-1127, 1996; Morzherin, Tarasov and Bakulev, Khim. Geterotsikl Soedin. 4:554-559, 1994; Morzherin, Bakulev, Dankova and Mokrushin, Khim. Geterotsikl Soedin 4:548-553, 1994; Shafran, Bakulev, Shevirin, and Kolobov, Khim. Geterotsikl. Soedin. 6:840-6, 1993; Dankova, Bakulev, and Morzherin, Khim. Geterotsikl. Soedin. 8:1106-1112, 1992; Bakulev, Lebedev, Dankova, Mokrushin, and Petrosyan, Tetrahedron 45(23):7329-7340, 1989; Kankova, Bakulev, Kolobov, Andosova, and Mokrushin, Khim. Geterotsikl, Soedin. 6:827-829, 1989; Dankova, Bakulev, Kolobov, Shishkina, Yasman, and Lebedev, Khim. Geterotsikl. Soedin 9:1269-1273, 1988; Bakulev, Kolobov, Grishakov, and Mokrushin, Izv. Akad. Nauk SSR, Ser. Khim. 1:193-195, 1988; Kolobov, Bakulev, Mokrushin, and Lebedev, Khim. Geterotsikl. Soedin 11:1503-1508, 1987; Bakulev, Dankova, Mokrushin, Sidorov, and Lebedev, Khim. Geterotsikl. Soedin. 6:845-849, 1987; Kolobov, Bakulev, and Mokrushin, Zh. Org. Khim. 23(5):1120-1122, 1987; Lebedev, Shevchenko, Kazaryan, Bakulev, Shafran, Kolobov, and Prosyan, Khim. Geterotsikl. Soedin. 5:681-689, 1987; Shafran, Bakulev, Mokrushin, and Validuda, Khim. Geterotsikl. Soedin. 5:691-696, 1986; Dankova, Bakulev, Mokrushin, and Shafran, Khim. Geterotsikl. Soedin, 10:1429-1430, 1985; and Shafran, Bakulev, Mokrushin, and Pushkareva, Khim. Geterotsikl. Soedin. 12:1696-1697, 1982; and Gewald and Hain, J. Prakt. Chem. 317(2):329-336, 1975.
The regulation of integrin linked kinase by phosphatidylinositol (3,4,5) trisphosphate is described by Delcommenne et al. (1998) Proc Natl Acad Sci 95:11211-6. Activated nitriles in heterocyclic synthesis are discussed in Kandeel et al. (1985) J. Chem. Soc. Perkin. Trans 1499. Oxidative transformation of pyrazole into triazole is discussed in Kandeel et al. (1986) J. Chem. Soc. Perkin. Trans 1379.